SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH ? steatosis with hepatocellular injury) with or without fibrosis. NAFLD is prevalent in obese and diabetic patients, and represents an independent risk factor for cardiovascular disease and mortality. Within the VA patient population, the prevalence of obesity/diabetes/NASH is higher than in the general population and represents a major clinical and economic burden. There are no proven medical therapies to prevent and treat NASH. Therefore, it is important to understand the mechanisms that contribute to NASH development, with the goal to identify novel targets for future drug development. The current application overviews published clinical and experimental evidence that growth hormone (GH) suppresses hepatic fat accumulation and prevents liver injury. Our published and unpublished data indicate GH mediates these effects directly at the level of the hepatocyte by enhancing STAT5B activity. Studies are outlined that will use hepatocyte-specific adenoviral-associated vector (AAV) delivery of transgenes in adult mice to test the HYPOTHESIS- Reduction in hepatocyte-specific GHR-mediated activation of the transcription factor, STAT5B, directly contributes to adult-onset NASH development and selective enhancement of hepatocyte-STAT5B activity will prevent and reverse NASH. The following Specific Aims (SA) will test this hypothesis. SA1- Determine if augmenting hepatocyte STAT5B activity can slow or prevent diet-induced steatosis and NASH development in the presence or absence of hepatocyte GHR-signaling and IGF1 production. SA2- Determine if the reduction in hepatic pSTAT5B, observed in diet-induced fatty livers, is due to the development of hepatic GH resistance. SA3 - Determine if enhancing the activity of hepatocyte STAT5B can reverse established diet- induced NASH. Endpoints examined include: 1) histopathologic assessment of hepatic steatosis and injury; 2) determination of hepatic lipid content and composition by gas chromatography- and liquid chromatography mass spectroscopy; 3) activation status of hepatic GH receptor-mediated downstream signals by Western blot analysis; 4) evaluation of hepatic expression of genes important in lipid and glucose processing by qPCR and Western blot analysis; 5) assessment of whole body insulin sensitivity and glucose tolerance, as well as, glucose/lipid utilization by indirect calorimetry. Completion of these studies will provide new information regarding how GH directly controls hepatocyte function to inhibit steatosis and prevent liver injury. This information could reveal novel drug targets to treat NASH.